Hyperactivity and Seizure Induced by Tricresyl Phosphate Are Isomer Specific and Not Linked to Phenyl Valerate-Neuropathy Target Esterase Activity Inhibition in Zebrafish.

Autor:	Knoll-Gellida A; Department of Life and Health Sciences, INSERM, Maladies Rares: Génétique et Métabolisme (MRGM), U1211, Université de Bordeaux, F-33615 Pessac, France., Dubrana LE; Department of Life and Health Sciences, INSERM, Maladies Rares: Génétique et Métabolisme (MRGM), U1211, Université de Bordeaux, F-33615 Pessac, France., Bourcier LM; Department of Life and Health Sciences, INSERM, Maladies Rares: Génétique et Métabolisme (MRGM), U1211, Université de Bordeaux, F-33615 Pessac, France., Mercé T; Department of Life and Health Sciences, INSERM, Maladies Rares: Génétique et Métabolisme (MRGM), U1211, Université de Bordeaux, F-33615 Pessac, France., Gruel G; Department of Life and Health Sciences, INSERM, Maladies Rares: Génétique et Métabolisme (MRGM), U1211, Université de Bordeaux, F-33615 Pessac, France., Soares M; Department of Life and Health Sciences, INSERM, Maladies Rares: Génétique et Métabolisme (MRGM), U1211, Université de Bordeaux, F-33615 Pessac, France., Babin PJ; Department of Life and Health Sciences, INSERM, Maladies Rares: Génétique et Métabolisme (MRGM), U1211, Université de Bordeaux, F-33615 Pessac, France.
Jazyk:	angličtina
Zdroj:	Toxicological sciences : an official journal of the Society of Toxicology [Toxicol Sci] 2021 Feb 26; Vol. 180 (1), pp. 160-174.
DOI:	10.1093/toxsci/kfab006
Abstrakt:	Environmental exposure to tricresyl phosphate (TCP) may lead to severe neurotoxic effects, including organophosphate (OP)-induced delayed neuropathy. TCP has three symmetric isomers, distinguished by the methyl group position on the aromatic ring system. One of these isomers, tri-ortho-cresyl phosphate (ToCP), has been reported for years as a neuropathic OP, targeting neuropathic target esterase (NTE/PNPLA6), but its mode of toxic action had not been fully elucidated. Zebrafish eleuthero-embryo and larva were used to characterize the differential action of the TCP isomers. The symmetric isomers inhibited phenyl valerate (PV)-NTE enzymatic activity in vivo with different IC50, while no effect was observed on acetylcholinesterase activity. Moreover, the locomotor behavior was also affected by tri-para-cresyl phosphate and tri-meta-cresyl phosphate, only ToCP exposure led to locomotor hyperactivity lasting several hours, associated with defects in the postural control system and an impaired phototactic response, as revealed by the visual motor response test. The electric field pulse motor response test demonstrated that a seizure-like, multiple C-bend-spaghetti phenotype may be significantly induced by ToCP only, independently of any inhibition of PV-NTE activity. Eleuthero-embryos exposed to picrotoxin, a known gamma-aminobutyric acid type-A receptor inhibitor, exhibited similar adverse outcomes to ToCP exposure. Thus, our results demonstrated that the TCP mode of toxic action was isomer specific and not initially related to modulation of PV-NTE activity. Furthermore, it was suggested that the molecular events involved were linked to an impairment of the balance between excitation and inhibition in neuronal circuits. (© The Author(s) 2021. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)
Databáze:	MEDLINE
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